Tang Feng-Lin, Zhang Xiao-Gang, Ke Ping-Yang, Liu Jie, Zhang Zhi-Juan, Hu Dan-Mei, Gu Juan, Zhang Hui, Guo Hao-Kun, Zang Qian-Wen, Huang Rui, Ma Yuan-Lin, Kwan Patrick
Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing 400016, China.
Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing 400016, China; Department of Neurology, Chongqing General Hospital, Chongqing Key Laboratory of Neurodegenerative Diseases, Chongqing 401147, China.
Neurobiol Dis. 2023 Jun 1;181:106103. doi: 10.1016/j.nbd.2023.106103. Epub 2023 Mar 29.
Epilepsy is considered to result from an imbalance between excitation and inhibition of the central nervous system. Pathogenic mutations in the methyl-CpG binding domain protein 5 gene (MBD5) are known to cause epilepsy. However, the function and mechanism of MBD5 in epilepsy remain elusive. Here, we found that MBD5 was mainly localized in the pyramidal cells and granular cells of mouse hippocampus, and its expression was increased in the brain tissues of mouse models of epilepsy. Exogenous overexpression of MBD5 inhibited the transcription of the signal transducer and activator of transcription 1 gene (Stat1), resulting in increased expression of N-methyl-d-aspartate receptor (NMDAR) subunit 1 (GluN1), 2A (GluN2A) and 2B (GluN2B), leading to aggravation of the epileptic behaviour phenotype in mice. The epileptic behavioural phenotype was alleviated by overexpression of STAT1 which reduced the expression of NMDARs, and by the NMDAR antagonist memantine. These results indicate that MBD5 accumulation affects seizures through STAT1-mediated inhibition of NMDAR expression in mice. Collectively, our findings suggest that the MBD5-STAT1-NMDAR pathway may be a new pathway that regulates the epileptic behavioural phenotype and may represent a new treatment target.
癫痫被认为是由中枢神经系统兴奋与抑制之间的失衡所致。已知甲基化CpG结合域蛋白5基因（MBD5）的致病性突变会导致癫痫。然而，MBD5在癫痫中的功能和机制仍不清楚。在此，我们发现MBD5主要定位于小鼠海马体的锥体细胞和颗粒细胞，且在癫痫小鼠模型的脑组织中其表达增加。MBD5的外源性过表达抑制了信号转导和转录激活因子1基因（Stat1）的转录，导致N-甲基-D-天冬氨酸受体（NMDAR）亚基1（GluN1）、2A（GluN2A）和2B（GluN2B）的表达增加，从而导致小鼠癫痫行为表型加重。通过过表达降低NMDARs表达的STAT1以及使用NMDAR拮抗剂美金刚，癫痫行为表型得到缓解。这些结果表明，MBD5的积累通过STAT1介导的对小鼠NMDAR表达的抑制影响癫痫发作。总体而言，我们的研究结果表明，MBD5-STAT1-NMDAR途径可能是调节癫痫行为表型的一条新途径，可能代表一个新的治疗靶点。
